Our laboratory and clinical research efforts have been devoted to studying the cellular immune reactivity against established cancers in experimental animals and in humans and the translation of these findings to the development of effective immunotherapies for patients with cancer. Our early studies demonstrated that the systemic administration of IL-2 could lead to durable objective cancer regressions in patients with metastatic melanoma or metastatic kidney cancer and ultimately led to the approval of IL-2 by the Food and Drug Administration as a treatment for patients with these metastatic cancers. These clinical studies of IL-2 administration led to studies to identify the immune cells capable of recognizing cancer. Attempts to generate lymphoid cells with specific anti-tumor activity led to the description of tumor infiltrating lymphocytes (TIL) in both mice and humans that could be grown from the stroma of solid tumors. These TIL have been used to develop adoptive cell transfer therapies. Adoptive cell transfer has several theoretical advantages compared to other immunotherapy approaches. In cell transfer therapies highly selected cells with high avidity for recognition of tumor antigens can be activated ex vivo to exhibit anti-tumor effector function, expanded to large numbers, and tested in vitro to identify the exact subpopulations and effector functions that are required for cancer regression in vivo. Perhaps most importantly it is possible to manipulate the host prior to the cell transfer to provide an altered environment for the transferred cells. Naturally occurring tumor infiltrating lymphocytes (TIL) expanded in vitro and administered melanoma in 56% of 194 patients including complete regressions in 24% of patients who remain ongoing disease-free 3 to 10 years later. To determine the antigens recognized by TIL we developed an approach based on deep exomic sequencing of the cancer and immunologic testing of TIL or peripheral lymphocytes to generate T-cells that recognized immunogenic mutations. TIL from 34 patients with metastatic melanoma recognized 78 random somatic mutations none of which were shared among different melanomas. We next extended these studies to patients with common epithelial cancers and showed that 81 of 99 (82%) patients with a variety of human cancer types including esophageal, colorectal, bile duct, gastric, pancreatic, ovarian, cervical and lung cancer contained T-cells that recognized 197 neoantigens all of which were unique except for KRAS (2 patients). Targeting unique cancer mutations has extended the reach of ACT immunotherapy and was used to mediate objective regressions in selected patients with chemorefractory metastatic cancers of the bile duct, colon, cervix, and breast. In addition to the use of naturally occurring mutation-reactive cells, we have genetically engineered autologous lymphocytes to express chimeric antigen receptors (CAR) for use in ACT immunotherapy that can mediate durable cancer regressions in 46% of heavily pretreated patients with refractory lymphoma. Autologous T-cells can be used to provide a highly personalized immunotherapy for cancer patients refractory to conventional cancer treatments.